This invention relates to a novel, convenient and economic process for producing alkali metal salts of certain penicillanic acid derivatives. More particularly, it relates to the production of alkali metal salts of 6-[2-phenyl-2-(imidoylaminoalkanoylamino)acetamido]penicillanic acids, a class of broad spectrum antibacterial agents especially useful against gram-negative microorganisms.
Belgian Pat. Nos. 803,094 and 810,266, granted February 1, 1974 and July 29, 1974, respectively, describe certain 6-[2-aryl-2-(imidoylaminoalkanoylamino)acetamido]penicillanic acids and various salts thereof, including alkali metal salts, which are valuable broad spectrum antibiotics, especially against gram-negative micro-organisms. The methods for alkali metal salt formation described therein comprise reacting the appropriate penicillanic acid derivative with an appropriate alkali metal salt (hydroxide, carbonate, bicarbonate, hydride, alkoxide) in an aqueous or non-aqueous medium and recovering the salt by lyophilization.
The relatively high polar nature of the herein described penicillanic acid derivatives, their tendency to undergo dimerization and oxidation to colored by-products and degradation of the .beta.-lactam ring in alkaline solutions renders the formation of alkali metal salts suitable for pharmaceutical usage without further purification difficult.
The alkali metal salts produced by the art described procedures are generally of poor quality as regards color of the salt. Solutions prepared therefrom are frequently of low stability as a result of auto-catalyzed degradation and ill-suited for the preparation of pharmaceutically elegant preparations required by the medical and pharmaceutical professions.
The formation of alkali metal salts of 6-acylamidopenicillanic acids, including those wherein the 6-acylamido group carries a basic substituent, e.g., an amino group as in 6-(.alpha.-aminophenylacetamido)penicillanic acid (ampicillin) has, for example, been achieved by a process which comprises treating the ampicillin in an organic solvent with a primary or secondary aliphatic amine, a cycloaliphatic or heterocyclic amine to form an amine salt and then adding an alkali metal compound (methoxide, iodide, phenoxide, thiocyanate, ethyl sodio-acetate) to precipitate the alkali metal salt (British Pat. No. 1,128,235).
British Pat. No. 1,060,034 describes a process for preparing alkali metal salts of ampicillin by reacting the triethylamine salt of ampicillin in an organic solvent with an alkali metal alkoxide.
U.S. Pat. No. 3,669,957 discloses the preparation of sodium ampicillin by reaction of the diethylamine salt of ampicillin in methylene chloride solution with sodium 2-ethylhexanoate and subsequent precipitation of the sodium salt by addition of acetonitrile to the solution.